The long term goal of this research program is to elucidate how axons drive Schwann cell ensheathment and myelination. We are investigating the role of neuregulin-1 (NRG1), a neuronal growth factor which regulates the entire Schwann cell lineage, including the binary choice between ensheathment and myelination in the PNS. The mechanisms by which type III NRG1 drives Schwann cell ensheathment and myelination remain poorly understood. NRG1 binds to erbB receptors on Schwann cells, activating the PI 3-kinase, PLC-3, and MAP kinase signaling pathways. Our general model is that Schwann cell survival, ensheathment and myelin wrapping all require NRG1-dependent activation of PI 3-kinase whereas other signaling pathways may drive the sequential expression of myelin-specific transcription factors (TFs). Using a recently generated transgenic mouse that expresses an activated, membrane targeted form of Akt1, we will investigate further how NRG1 drives axon ensheathment, myelination, and survival. Specifically, we will: i) investigate whether Akt is a primary effector of PI 3-kinase- dependent survival and ensheathment by analyzing mice deficient in Akt isoforms and by expressing activated Akt in Schwann cells interacting with NRG1 deficient neurons, ii) characterize the role(s) of the TORC1 and TORC2 pathways in ensheathment and myelination, and iii) analyze whether Akt cooperates with other signals, including NFAT, during myelination, by crossing transgenic mice expressing activated Akt and NFAT transgenes and examine potential cooperative effects on myelination. These studies should provide important insights into how type III NRG1 on the axon drives survival, ensheathment and myelination by Schwann cells. Relevance: These studies seek to identify signals that promote myelin sheath formation, the cellular insulation that surrounds nerve fibers and is critical for their proper function and long term integrity. Findings in this study may therefore have important implications for the pathogenesis of disorders of myelinated fibers, including neuropathies, and lead to new therapeutic strategies to promote their repair. PUBLIC HEALTH RELEVANCE: This project investigates the mechanisms by which type III Neuregulin 1 on the axon drives Schwann cell ensheathment and myelination, focusing in particular on the role of the PI 3- kinase pathway, and its effectors, in these events using myelinating cocultures and genetic mouse models.